Orodispersible tablets containing fexofenadine

ABSTRACT

The present invention concerns orodispersible tablets, which are able to disintegrate in the buccal cavity upon contact with saliva by formation of an easy-to-swallow suspension, in less than 60 seconds, preferably in less than 40 seconds, containing fexofenadine in the form of coated granules, and a mixture of excipients comprising at least one disintegrating agent, a soluble diluent agent, a lubricant and optionally a swelling agent, a permeabilising agent, sweeteners, flavoring agents and colors; the process for obtaining such orodispersible tablets and the coated granules incorporated therein and the use of said orodispersible tablets in the treatment of seasonal allergic rhinitis.

FIELD OF THE INVENTION

The present invention concerns orodispersible tablets comprising coatedgranules of fexofenadine. The invention also concerns said coatedgranules of fexofenadine, a process for the preparation thereof and theuse of said orodispersible tablets.

In the context of the present invention, the term “orodispersibletablets” means tablets which are able to disintegrate in the buccalcavity in less than 60 seconds, preferably in less than 40 seconds, uponcontact with saliva by formation of an easy-to-swallow suspension.

The disintegration time corresponds to the time between the moment whenthe tablet is placed in the buccal cavity in contact with saliva and themoment when the suspension (resulting from the disintegration withoutchewing of the tablet) is swallowed

BACKGROUND OF THE INVENTION

Fexofenadine is a well known synthetic antiallergenic with the chemicalname(±)-4-[1-hydroxy-4-[4(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]α,α-dimethylbenzeneacetic acid.

Fexofenadine, a metabolite of terfenadine, is an antihistamine withselective peripheral H1-receptor antagonist activity.

Fexofenadine is known from e.g. U.S. Pat. No. 4,254,129. It isacknowledged in the art and is commercially available, in particular asan oral tablet or capsule, under the trade name Allegra®.

The tablets, commercially available under the trade name Allegra®contain 30, 60, or 180 mg fexofenadine hydrochloride (depending on thedosage) and, as excipients, croscarmellose sodium, magnesium stearate,microcrystalline cellulose and pregelatinized starch. Said tablets arecoated with a film coating based on hydroxypropyl methylcellulose,mixture of iron oxides, polyethylene glycol, povidone, silicone dioxide,and titanium dioxide.

Fexofenadine is highly active via oral administration. While numerouspharmaceutical compositions for oral administration have been proposed,there still exists a need for commercially acceptable fexofenadineformulations for oral administration with good patient convenience andacceptance, especially for children or the elderly.

One particular difficulty in the formulation of fexofenadine in oralpharmaceutical compositions is its unpleasant, strong bitter taste andaftertaste.

Another difficulty in the formulation of fexofenadine in oralpharmaceutical compositions is the low solubility of fexofenadine,especially in gastric conditions (solubility of 0.2 mg of fexofenadineHCl per ml of pH 1.2 aqueous buffer solution).

It is therefore highly desirable to develop coated granules, containingfexofenadine, which have taste-masking properties while permitting rapidrelease of the active substance from the granules and allowing rapidabsorption in the body after oral administration.

Furthermore, some patients, especially children and the elderly,experience difficulties swallowing the tablets, even with liquids.

It is estimated that 50% of the population have problems swallowing thetablets. This leads to poor, or even noncompliance, with the treatmentand thus has a negative impact on the efficiency of the treatment (H.Seager, 1998, J. Pharm. Pharmacol. 50, 375-382).

Oral disintegrable multiparticulate tablets have already been describedin U.S. Pat. No. 5,464,632, U.S. Pat. No. 6,106,861, WO 00/27357 andWO00/51568, the contents of which are hereby incorporated by reference.The active ingredient is in the form of coated microcrystals or coatedmicrogranules.

Up to now, no oral formulations of fexofenadine exist which arespecifically suitable for patients having difficulties when swallowingor for patients taking the drugs with no liquids.

It is thus highly desirable to remedy this situation and to develop anorodispersible tablet, containing fexofenadine, which has taste-maskingproperties and presents a pleasant palatability such that theadministration of the tablet is not unpleasant for the patient and whichallows the obtaining of pharmacokinetic parameters at leastbioequivalent to those which are obtained with conventional oralformulations of fexofenadine, for example tablets such as thoseavailable under the trademark Allegra®.

The Applicant has now surprisingly found that these characteristics canbe obtained by formulating a tablet containing fexofenadine as activeingredient in the form of coated granules, and a mixture of excipientscontaining at least one disintegrating agent, a soluble diluent agentand a lubricant, and optionally a swelling agent, an antistatic agent, apermeabilising agent, sweeteners, flavoring agents and colors.

The present invention relates to orodispersible tablets which are ableto disintegrate in the buccal cavity upon contact with saliva byformation of an easy-to-swallow suspension, in less than 60 seconds,preferably in less than 40 seconds, such tablets containing fexofenadineas active ingredient in the form of coated granules, and a mixture ofexcipients comprising at least one disintegrating agent, a solublediluent agent, a lubricant and optionally a swelling agent, anantistatic agent, a permeabilising agent, sweeteners, flavoring agentsand colors.

Surprisingly, although the tablets according to the inventiondisintegrate in the buccal cavity and present a release of the activeingredient which is equivalent to the conventional formulation, theynevertheless have a pleasant taste.

Furthermore, the orodispersible tablets of the invention are found toshow high stability and physical integrity, e.g. during storage,handling, packaging and the like, while maintaining very gooddisintegration performance.

Fexofenadine may be used in the form of its racemate or a singleenantiomer, in free base form or in acid addition salt form of theracemate or one of its single enantiomers. An acid addition salt formmay be prepared from the free base form in a conventional manner andvice-versa. Examples of suitable acid addition salt forms includehydrochloride, lactate and ascorbate, preferably hydrochloride.Fexofenadine in the form of a hydrochloride salt is preferred.

In a preferred embodiment, fexofenadine particles present a particlesize such that 100% of the particles have an average size of less than20 μm.

In the tablets according to the invention, fexofenadine in anyone ofsaid forms is present as coated granules.

In the present patent application, the term “fexofenadine” is employedfor designating anyone of its specific forms.

According to an advantageous embodiment, the tablet according to theinvention, has a hardness of not less than 15 N, when measured with thetest method of the European Pharmacopeia (2.9.8).

According to an advantageous embodiment, the tablet according to theinvention contains coated granules of fexofenadine, or one of itspharmaceutically acceptable salts, and a mixture of excipients, theratio of the mixture of excipients to the coated granules is 0.4 to 9,preferably 1.5 to 5 and even more preferably 2 to 3 parts by weight, themixture of excipients comprising:

-   -   at least one disintegrating agent,    -   a soluble diluent agent,    -   a lubricant,    -   and optionally a permeabilising agent, a swelling agent, an        antistatic agent, sweeteners, flavoring agents and colors.

The disintegrating agent is selected from the group consisting ofcroscarmellose, available as e.g. Ac-di-sol®, crospovidone available ase.g. Kollidon CL®, and mixtures thereof.

According to an advantageous embodiment of the invention, the solublediluent agent used in the tablets presents binding properties. Thesoluble diluent agent with binding properties consists of a polyolhaving less than 13 carbon atoms and being either in the form of adirectly compressible product with an average particle size of 100 to500 μm, or in the form of a powder with an average particle size of lessthan 100 μm, this polyol preferably being selected from the groupcomprising mannitol, xylitol, sorbitol and maltitol, it being Understoodthat sorbitol cannot be used alone and that, in the case where there isonly one soluble diluent agent with binding properties, it is used inthe form of the directly compressible product, whereas in the case wherethere are at least two soluble diluent agents with binding properties,one is present in the directly compressible form and the other ispresent in powder form, it then being possible for the polyols to be thesame, the ratio of directly compressible polyol to powder polyol being99/1 to 20/80, preferably 80/20 to 20/80.

The proportion of disintegrating agent is from 3 to 15% by weight,preferably 5 to 15% by weight, in the case of a mixture, eachdisintegrating agent being comprised between 1 and 10% by weight,preferably 5 to 10% by weight, and the proportion of soluble diluentagent being 30 to 90% by weight, preferably 40 to 60% by weight, basedin each case on the weight of the tablet.

The lubricant is selected from the group consisting of magnesiumstearate, stearic acid, sodium stearyl fumarate, micronisedpolyoxyethyleneglycol (micronised Macrogol 6000), leukine, sodiumbenzoate and mixtures thereof.

The amount of lubricant is from 0 to 3%, preferably from 1 to 2% byweight, based on the weight of the tablet.

The lubricant can be dispersed within the mixture of excipients, oraccording to an advantageous embodiment, sprayed over the outer surfaceof the tablet. Thus, according to an advantageous embodiment of thetablets of the invention, the lubricant is in powder form and is, atleast in part, disposed on the surface of the tablets.

The permeabilising agent allows the creation of a hydrophilic networkwhich facilitates the penetration of saliva and hence assists thedisintegration of the tablet.

The permeabilising agent is selected from the group comprisingespecially silica with a high affinity for aqueous solvents, such ascolloidal silica (Aerosil®), precipitated silica (Syloïd® FP 244),maltodextrins, β-cyclodextrins and mixtures thereof.

The amount of permeabilising agent is between 0 and 5%, preferably from0.5 to 2% by weight, based on the weight of the tablet.

A swelling agent can be incorporated in the mixture of excipients. Saidswelling agent is selected from the group consisting of starch, modifiedstarch or microcristalline cellulose.

An antistatic agent can be incorporated as a flow aid, said antistaticagent being selected from the group consisting of micronised or nonmicronised talc, fumed silica (Aerosil® R972), colloidal silica(Aerosil®200), precipitated silica (Syloïd® FP 244), and mixturesthereof.

The sweetener which can be included in the mixture of excipients, can beselected from the group consisting of especially aspartam, potassiumacesulfame, sodium saccharinate, neohesperidin dihydrochalcone,sucralose, monoammonium glycyrrhizinate, and mixtures thereof.

The flavorings and colors are those conventionally used in pharmacy forthe preparation of tablets.

The present invention also relates to the coated granules offexofenadine or one of its pharmaceutically acceptable salts.

The taste-masking of fexofenadine is achieved by coating granulatedmicrocrystals of fexofenadine with one or more polymers.

According to an advantageous embodiment of the invention, the granulesof fexofenadine, or one of its pharmaceutically acceptable salts, arecharacterized in that the granules are coated and that they contain:

-   -   microcrystals of fexofenadine, or one of its pharmaceutically        acceptable salts,    -   at least one binder,    -   optionally a diluent agent, an antistatic agent, a sweetening        agent and/or a coloring agent.

Furthermore, the granulation excipients can also include disintegratingagents and/or surfactants.

The binder is selected from the group consisting of cellulosic polymers,such as ethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose, acrylic polymers, such as insoluble acrylateammoniomethacrylate copolymer, polyacrylate or polymethacryliccopolymer, povidones, copovidones, polyvinylalcohols, alginic acid,sodium alginate, starch, pregelatinized starch, sucrose and itsderivatives, guar gum, polyethylene glycol, preferably an acrylicpolymer, most preferably Eudragit® E100, and mixtures thereof.

Optionally, in order to enhance the granulation of the fexofenadine orone of its pharmaceutically acceptable salts, a diluent agent is used.

The diluent agent is selected from the group consisting ofmicrocrystalline cellulose, sucrose, dicalcium phosphate, starches,lactose and polyols of less than 13 carbon atoms, such as mannitol,xylitol, sorbitol, maltitol, pharmaceutically acceptable amino acids,such as glycin, and their mixtures.

The antistatic agent, which can be used as flow aid, is selected fromthe group consisting of micronised or non micronised talc, fumed silica(Aerosil® R972), colloidal silica (Aerosil200), precipitated silica(Syloïd® FP244) and mixtures thereof.

Conventional pharmaceutically acceptable sweetening agents and/orcolouring agents can be incorporated into the granules of fexofenadine.

In a particular embodiment, the granule of fexofenadine or one of itspharmaceutically acceptable salts, is in the form of a core ofgranulated microcrystals of fexofenadine, coated with at least one layercomprising fexofenadine.

Said coated core is characterized in that the core and the layercomprise each from 70% to 95%, preferably 80% to 95% by weight offexofenadine, or one of the pharmaceutically acceptable salts thereof,the balance to 100% being formed with at least one binder, and that saidcoated core is advantageously a sphere. Such a specific structure haspreviously been described by the Applicant in the French patentapplication FR 00 14803.

According to another embodiment of the invention, the granules comprise:

-   -   from 10% to 95%, preferably from 50% to 70% of fexofenadine, or        one of the pharmaceutically acceptable salts thereof,    -   at most 20%, preferably at most 10% by weight of the binder,        relative to the weight of fexofenadine, or one of the        pharmaceutically acceptable salts thereof,    -   at most 5%, preferably 2% by weight of the antistatic agent,        relative to the weight of said granules    -   optionally a diluent agent for the balance to 100%.

In order to ensure efficient taste masking, and a dissolution profile ofthe active substance such that more than 70% of the active substance isreleased in 30 minutes, preferably more than 90% is released in 30minutes, the granules are coated with a coating composition containingat least one coating polymer selected from the group consisting ofcellulosic polymers, acrylic polymers and their mixtures.

Among the cellulosic polymers, ethylcellulose, hydroxypropylcellulose(HPC) and hydroxypropylmethylcellulose (HPMC), are advantageously used.

Among the acrylic polymers, insoluble acrylate ammoniomethacrylatecopolymer (Eudragit® RL100 or RS100 or Eudragit® RL30D or RS30D),polyacrylate (Eudragit®NE30D), or methacrylic copolymers (Eudragit®L100-55 or Eudragit® L30D, Eudragit® E100, Eudragit® EPO . . . ) areadvantageously used, alone, in combination or in admixture withpH-dependent polymers. Eudragit® E100 or a mixture of Eudragit® EPO andEudragit®NE30D are preferred.

In a preferred embodiment, the binder and the coating polymer are thesame polymer.

The prepared coating liquid is either water-based or prepared withorganic solvents. According to an advantageous embodiment, this coatingliquid is suitable to be sprayed with conventional spray layeringequipment, as for example a fluidized bed equipped with a top insert orbottom (würster) insert.

Optionally permeabilising agents, plasticizers, soluble agents,disintegrating agents and surfactants are added as coating additives.

The plasticizer is selected in the group consisting of triacetine,triethylacetate, triethylcitrate (Eudraflex®), ethylphthalate, ormixtures thereof. The plasticizer is used in proportions of at mostabout 30%, preferably 10% by weight of the coating polymers.

The soluble agents are selected in particular among the polyols havingless than 13 carbon atoms.

The disintegrating agent or a surfactant which could be added during thegranulation and the coating steps allow improved dissolution.

The surfactant may be an anionic, nonionic, cationic or amphotericsurfactant.

The disintegrating agent is selected from the group consisting ofcroscarmellose, available as e.g. Ac-di-sol®, crospovidone available ase.g. Kollidon CL®, and mixtures thereof.

The particle size range of coated granules comprising fexofenadine, orone of its pharmaceutically acceptable salts is adapted for obtaining aneffective taste masking with an acceptable coating factor and a goodmouthfeel.

Advantageously the coated granules according to the invention have aparticle size distribution between 150 μm and 500 μm, preferably between150 μm and 425 μm, such that at least 50%, preferably at least 70% ofthe granules have a particle size ranging between 150 and 425 μm andless than 15% of the granules have a particle size less than 150 μm. Theparticle sizes are measured according to conventional methods,preferably by sieving.

A granulation step is needed in order to obtain such particle sizedistribution.

In a particular embodiment, the coated granules according to theinvention comprise:

-   -   from 10% to 95%, preferably 40 to 75% of granules of        fexofenadine, or one of its pharmaceutically acceptable salts,        preferably fexofenadine HCl,    -   from 5 to 90%, preferably 10 to 70% and even more preferably        from 25 to 55% of a coating polymer, preferably Eudragit® E100,        the percentages being expressed by weight relative to the weight        of the granules of fexofenadine, or one of its pharmaceutically        acceptable salts,    -   from 0 to 10% of a permeabilising agent, preferably colloidal        silica, the percentages being expressed by weight relative to        the weight of the coating polymer.

Determination of workable proportions in any particular instance willgenerally be within the capability of the person skilled in the art. Allindicated proportions and relative weight ranges described above areaccordingly to be understood as being indicative of preferred orindividually inventive teachings only and not as limiting the inventionin its broadest aspect.

Details concerning any of the excipients of the invention may be foundin Fiedler, H. P. “Lexikon der Hilfsstoffe für Pharmazie, Kosmetik undangrenzende Gebiete”, Editio Cantor Verlag Aulendorf, Aulendorf, 4threvised and expanded edition (1996); “Handbook of PharmaceuticalExcipients”, 2nd Edition, Editors A. Wade and P. J. Weller (1994), Jointpublication of American Pharmaceutical Association, Washington, USA andThe Pharmaceutical Press, London, England; or may be obtained from therelevant manufacturers, the contents of which are hereby incorporated byreference.

The invention also relates to a process for the preparation of coatedgranules of fexofenadine, which comprises the successive stepsconsisting in:

-   -   dry mixing the microcrystals of fexofenadine or one of its        pharmaceutically acceptable salts optionally with an antistatic        agent and/or a diluent agent;    -   granulating the mixture obtained in the above step by spraying        of a solution or suspension of at least one binder,    -   optionally applying a layer over the thus obtained granules by        spraying thereon a suspension, or a solution comprising        fexofenadine, or one of its pharmaceutically acceptable salts        with at least one binder,    -   coating the thus obtained granules with a suspension of a        coating composition,    -   drying the thus obtained coated granules.

The invention also concerns a process for preparing orodispersibletablets comprising coated granules of fexofenadine, or one of itspharmaceutically acceptable salts.

The process comprises the successive steps consisting in:

-   -   dry mixing the microcrystals of fexofenadine, or one of its        pharmaceutically acceptable salts, optionally with an antistatic        agent, a diluent agent, a permeabilising agent, a sweetening        agent and/or a coloring agent;    -   granulating the thus obtained mixture by spraying thereon a        solution or a suspension of at least one binder,    -   optionally applying a layer over the thus obtained granules by        spraying thereon a suspension, or a solution comprising        fexofenadine, or one of its pharmaceutically acceptable salts        with at least one binder.    -   coating the thus obtained granules by spraying thereon a        suspension, a dispersion or a solution of the coating        composition,    -   drying the thus obtained coated granules,    -   dry mixing coated granules and a mixture of excipients        consisting of at least one disintegrating agent, a soluble        diluent agent, and optionally a lubricant, a permeabilising        agent, a swelling agent, sweeteners, an antistatic agent,        flavorings and colors,    -   compressing the mixture of coated granules and excipients into a        tablet.

The lubricant can be mixed with the excipients for the tablet, but canadvantageously be sprayed on the surface of the punches beforetabletting.

In this process the mixing, granulating and coating steps can beperformed in different or in the same equipment, each step beingperformed in the presence of a mixture of excipients which are identicalor different.

For granulating, high shear mixer, planetary mixer or fluidized bed withinsert used for bottom spray, granulation, tangential spray granulation,top spray granulation can be used, bottom spray granulation beingpreferred.

In an advantageous embodiment, each step is performed on a fluidizedair-bed, such as for example, but not limited to Glatt GPCG-1, GPCG-3,GPCG-5 or GPCG 120.

For coating, bottom, top and tangential spray methods can be used aswell as layering method, bottom spray method of coating being preferred.

For compressing the mixture of coated granules and excipients into atablet, various punches may be used, with diameters comprised between 8and 17 mm, depending upon the dosage of the tablet.

Various shapes may be used, such as for example, flat shape,advantageously with bevelled edges or polo punches.

The orodispersible tablets of the present invention show rapiddisintegration in the buccal cavity upon contact with saliva withoutchewing, in less than 60 seconds, preferably in less than 40 seconds,have a pleasant taste and palatability and thus have particularly goodpatient convenience and patient acceptance due to their increased easeof administration and ingestion.

In addition the tablets of the invention show surprisingly high physicalstability and are easy to handle and package.

According to a preferred embodiment, the tablet of the inventionpresents the following composition:

-   -   granules of Fexofenadine HCl coated with Eudragit® E100,    -   and a mixture of excipients consisting of Eudragit® E100,        mannitol powder, mannitol granular, Crospovidone, precipitated        silica, sweeteners and flavors.

For the preparation of said tablets, isopropanol is used as solvent andremoved during the coating and granulation processes.

According to an advantageous embodiment, the tablet of the invention hasthe following composition:

Fexofenadine Coated Granules Fexofenadine HCl 40-80% Eudragit ® E10020-60% Precipitated silica  0-5%the percentages being calculated by weight of coated granules,

Excipients for the Formulation of the Tablet Fexofenadine coatedgranules 10-45% Mannitol powder and/or granular 50-90% Crospovidone 2-15% Precipitated silica  0-5% Magnesium stearate  0-5% Sucralose 0-5% Flavors  0-2%the percentages being calculated by weight of the tablet.

For the preparation of said tablets, isopropanol is used as solvent andremoved during the coating and granulation processes.

The tablets are particularly effective in treating seasonal allergicrhinitis, in adults and children 6 years of age and older.

The present invention also concerns-the use of a coated granules offexofenadine with a mixture of excipients, as described above, for themanufacture of a medicament for the treatment of symptoms associatedwith seasonal allergic rhinitis.

The present invention relates also to methods for the treatment ofsymptoms associated with seasonal allergic rhinitis, in which thetablets of fexofenadine according to the invention are orallyadministered.

Symptoms treated effectively include sneezing, rhinorrhea, itchynose/palate/throat, itchy/watery, rhinitis.

The utility of the tablets of the present invention may be observed instandard bioavailability tests or standard animal models, for exampleascertaining dosages of the present tablets giving blood levels offexofenadine hydrochloride equivalent to blood levels having atherapeutical effect on administration of known fexofenadine oral dosageforms, e.g. a tablet.

The appropriate dosage will, of course, vary depending upon, forexample, the host and the nature and severity of the condition beingtreated. However, in general satisfactory results in animals areindicated to be obtained by daily treatments. In humans an indicateddaily dosage is in the range from about 10 mg to about 500 mg per day,preferably from 30 mg to 180 mg, conveniently administered, for example,in divided doses up to four times a day or once daily. Preferreddosages, expressed as fexofenadine HCl, for children 6 to 11 years ofage are about 30 mg two times a day, and for adults and children 12years of age and older from about 60 mg two times a day, or 180 mg oncea day.

The invention is illustrated more in detail in the following examples.

EXAMPLES

Particle size of Fexofenadine HCl used for the manufacture of granulesof examples 1 to 4 is measured with conventional laser equipment.

Particle size distribution has following characteristics: D_(10%)  2.1μm D_(50%)  5.3 μm D_(90%) 11.1 μm

In the examples below, the following excipients are used:

-   -   Methacrylic polymer sold under tradename Eudragit®EPO or        Eudragit® E100.    -   Polyacrylate sold under the tradename Eudragit® NE30D.    -   Mannitol powder    -   Mannitol granular 300    -   Sucralose    -   Aspartam    -   Peppermint, wildberry as flavoring agents    -   Precipitated silica sold under the name Syloïd FP244    -   Polyvinylpyrrolidone sold under the name PVP K90

Examples 1 to 4 relate to the preparation of coated granules offexofenadine.

Example 1

Granulating Step

500 g of fexofenadine HCl mixed with 15 g of Syloïd FP 244 weregranulated in a fluidized bed with 465 g of a mixture of EudragitEPO/Eudragit NE30D (50/50) in water at 16% (weight/weight).

Coating Step:

The thus obtained granules were coated in a fluidized bed equipped witha top insert, by spraying thereon a dispersion of 465 g of a mixture ofEudragit EPO/Eudragit NE30D (50/50) in water at 16% (weight/weight).

The amount of coating was of 12.5% by weight with respect to the weightof the granules of fexofenadine HCl.

The dissolution rates of the thus obtained coated granules were measuredwith the following method: Apparatus USP Apparatus II (Paddle method)Speed 50 rpm Volume 900 mL of HCl 0.001 N pH 3.0* Temperature 37.0° C. ±0.5° C. Sampling (5 mL) 2.5, 7.5, 15, 30 and 60 minutes HPLC DetectionUV at 220 nm HPLC column Zorbax SB-Phenyl, 5 μm, 4.6 × 250 mm. Injectionvolume 20 μL Mobile Phase Acetonitrile: 0.03 M Acetic acid containingTriethylamine pH 5.25 (36:64). Dissolution medium HCl 0.001 N adjustedto pH 3.0 ± 0.05 (if necessary) with o-Phosphoric acid.

The results are given in the following table 1: TABLE 1 Dissolvedfexofenadine in % (w/w)  5 minutes 55% 10 minutes 70% 15 minutes 75% 30minutes 85%

More than 80% of fexofenadine is dissolved after 30 minutes,taste-masking is efficient.

Example 2

Granulating Step

500 g of fexofenadine HCl mixed with 15 g of Syloïd FP244 weregranulated in a fluidized bed with 30 g of an aqueous solution of PVPK90 at 8% (weight/weight).

Coating Step:

The thus obtained granules were coated in a fluidized bed equipped witha top insert, by spraying thereon a mixture of Eudragit EPO/EudragitNE30D (60/40) in water at 16% (weight/weight)

The amount of coating was of 40% by weight with respect to the weight ofthe granules of fexofenadine HCl.

The particle size distribution (Sieve method) is given in the followingtable. TABLE 2 Sieve operture After Granulating step After Coatingstep >0.500 mm 14.5% 5.7%   0.425 mm-0.500 mm 13.0% 24.1%   0.355mm-0.425 mm 20.0% 9.5%   0.250 mm-0.355 mm 30.5% 28.9%   0.150 mm-0.250mm 21.5% 31.5% <0.150 mm 0.5% 0.3%

The dissolution rates of said granules were measured as indicated inexample 1 above.

The results are given in the following table 3: TABLE 3 Dissolvedfexofenadine in % (w/w)  5 minutes 65% 10 minutes 85% 15 minutes 100% 30minutes 100%

More than 80% of fexofenadine is dissolved after 30 minutes,taste-masking is efficient.

Example 3

Granulating Step

1000 g of fexofenadine HCl mixed with 30 g of Syloïd FP 244 weregranulated in a fluidized bed equipped with a Wurster insert with 1 500g of an solution of Eudragit E100 in isopropanol at 12% (weight/weight).

Coating Step:

The thus obtained granules were coated in a fluidized bed equipped witha top insert, by spraying thereon a polymeric dispersion of 3 900 g ofEudragit E100 in isopropanol at 12% (weight/weight) containing 1% ofSyloïd FP 244.

The amount of coating was of 38% by weight with respect to the weight ofthe granules of fexofenadine HCl.

The particle size distribution (Sieve method) is given in the followingtable. TABLE 4 Sieve operture Coated granules >0.600 mm   0%   0.500mm-0.600 mm  1.0%   0.425 mm-0.500 mm  9.2%   0.355 mm-0.425 mm 18.6%  0.250 mm-0.355 mm 36.2%   0.150 mm-0.250 mm 30.2%   0.090 mm-0.150 mm 3.4% <0.090 mm  1.4%

The dissolution rates of said granules were measured as indicated inexample 1 above.

The results are given in the following table 5: TABLE 5 Dissolvedfexofenadine in % (w/w)  5 minutes 55% 10 minutes 85% 15 minutes 95% 30minutes 100%

More than 80% of fexofenadine is dissolved after 30 minutes,taste-masking is efficient.

Example 4

Granulating Step

1000 g of fexofenadine HCl mixed with 30 g of Syloïd FP 244 weregranulated in a planetary mixer with 400 g of an solution of EudragitE100 in isopropanol at 12% (weight/weight).

Coating Step:

The obtained granules were coated in a fluidized bed equipped with aWurster insert, by spraying thereon a solution of Eudragit E100 inisopropanol at 10% (weight/weight) containing 1% of Syloïd FP 244.

The amount of coating was of 30% by weight with respect to the weight ofthe granules of fexofenadine HCl.

The dissolution rates of said granules were measured as indicated inexample 1 above.

The results are given in the following table 6: TABLE 6 Dissolvedfexofenadine in % (w/w)  5 minutes 40% 10 minutes 80% 15 minutes 95% 30minutes 100%100% of fexofenadine is dissolved after 30 minutes, taste-masking isefficient.

Examples 5-8 relate to the preparation of tablets.

Example 5

Three types of tablets T₁, T2, T3 were prepared using coated granules offexofenadine presenting different coating ratios. The coated granules offexofenadine were obtained as in example 3 above but using the threedifferent coating ratios of 30, 35 and 40. Then, an amount of each typeof said coated granules corresponding to 180 mg of fexofenadine HCl wasthoroughly blended for 15 minutes with the following tablet excipients.Crospovidone  10% Silica 0.5% Magnesium stearate 0.5% Aspartame   2%Flavor   1% Mannitol powder(60 μm)/granular (330 μm) (2/1) qs 100%

The percentages are expressed as percentage of the total weight of atablet.

The homogeneous obtained blend was introduced in a tabletting machineequipped with 14 mm-diameter polo shape punches.

These tablets T1, T2 and T3 were obtained.

For each tablet thus obtained, the weight, hardness, disintegrating timein mouth, mouthfeel and taste were measured.

The results are displayed in the table 7 TABLE 7 Tablets T1 T2 T3 Coatedgranule ratio   30   35   40 (% by weight) Weight   920 mg   780 mg  690 mg Hardness   44 N   39 N   45 N Disintegration time 15-20 sec.15-20 sec 20-25 sec. in mouth Mouthfeel Complies Complies Complies TasteComplies Complies CompliesT1, T2, T3 present an acceptable dissolution rate with good taste andpleasant mouthfeel and disintegrate in buccal cavity in less than 30seconds.

Example 6

As in example 5, three types of tablets (T4, T5, T6) presenting coatedgranules of fexofenadine with coating ratios of 30, 35, 40 were preparedbut using an amount of fexofenadine HCl equivalent to 30 mg per tablet.

The homogeneous obtained blend was introduced in a tabletting machineequipped with polo shape punches as described in the table.

Results are displayed in the table 8 TABLE 8 Tablets T4 T5 T6 Coatedgranule ratio   30   35   40 (% by weight) Punch diameter    8 mm    7mm    6 mm Weight   153 mg   131 mg   115 mg Hardness   44 N   39 N   45N Disintegration time 15-20 sec. 15-20 sec 20-25 sec. in mouth MouthfeelComplies Complies Complies Taste Complies Complies CompliesTablets T4, T5 and T6 present an acceptable taste and pleasant mouthfeeland disintegrate in buccal cavity in less than 30 seconds.

Example 7

Tablets T7 according to the formula of T2 of example 5 are manufactured,using a ratio of Mannitol powder/Mannitol granular ratio of 1/1,containing an amount of fexofenadine HCl equivalent to 180 mg pertablet.

The homogeneous obtained blend was introduced in a tabletting machineequipped with 14 mm-diameter polo shape punches.

The disintegration time in the mouth, the mouthfeel and taste wereevaluated.

The results are displayed in the table 9. TABLE 9 Tablets T7Disintegration time in mouth 25 sec. Mouthfeel Complies Taste CompliesTablets T7 with a mannitol powder/granular ratio of 1/1 (w/w) present agood taste and pleasant mouthfeel and disintegrate in buccal cavity inless than 30 seconds.

Example 8

Three types of tablets (T8, T9, T10 ) according to the formula T2 ofexample 5 were manufactured but using three different ratios ofcrospovidone of 5, 7.5 and 10% by weight.

The homogeneous obtained blend was introduced in a tabletting machineequipped with 14mm-diameter polo shape.

Tablets T8, T9 and T10 were thus obtained. The disintegrating time inmouth, the hardness, the mouthfeell and taste were evaluated, theresults are displayed in table 10. TABLE 10 Tablets T8 T9 T10Crospovidone ratio    5  7.5   10 (% by weight) Hardness   44 N   45 N  45 N Disintegration time 20-25 sec. 20-25 sec 20-25 sec. in mouthMouthfeel Complies Complies Complies Taste Complies Complies CompliesTablets T8, T9 and T10 present an acceptable taste and pleasantmouthfeel and disintegrate in buccal cavity in less than 30 seconds.

Exemple 9 Pharmacokinetic Studies

A bioequivalence study was conducted with two tablets (T11 and T12)according to the invention versus Allegra® 180 mg (Reference).

15 subjects received T11 versus Reference and 13 subjects received T12,each versus Reference

The respective compositions of T11 and T12 are given below: FexofenadineHCl coated granules T11 T12 Fexofenadine HCl 48.4% 58.2% Eudragit E10047.4% 37.7% Silica 4.2% 4.1%

Tablets Coated granules corresponding to  30% 180 mg of Fexofenadine HClCrospovidone   5% Silica 0.5% Magnesium stearate   1% Sucralose   2%Flavor 0.2% Mannitol powder(60 μm)/granular (330 μm) (1/1) qs 100%

Said tablets were prepared according to the process of example 5 above.The tablets (Prototype and Reference) were administered to fastingpatients. Pharmacokinetic parameters obtained for each prototype A and Band Reference are listed in tables 11 and 12: TABLE 11 Test 1 (n =15)-mean values AUC (CV) Cmax (CV) Tmax (CV) Reference 3132.2 453.8 2.0T11 3804.4 571.2 2.9 (% as exp. versus reference) (121) (126) (144)T11 under fasting conditions has slightly higher bioavailabilityrelative to the reference.

TABLE 12 Test 2 (n = 13)-mean values AUC Cmax Tmax Reference 3017.0457.3 2.2 T12 3047.1 409.8 2.6 (% as exp. versus reference) (101) (90)(115)T12 under fasting is bioequivalent relative to the reference tablet.

1-13. (canceled)
 14. Granules of fexofenadine, or one of itspharmaceutically acceptable salts, wherein the granules are coated andcontain: microcrystals of fexofenadine, or one of its pharmaceuticallyacceptable salts, at least one binder selected from the group consistingof cellulosic polymers, such as ethylcellulose, hydroxypropylcelluloseand hydroxypropylmethylcellulose, acrylic polymers such as insolubleacrylate ammoniomethacrylate copolymer, polyacrylate or polymethacryliccopolymer, povidones, copovidones, polyvinylalcohols, alginic acid,sodium alginate, starch, pregelatinized starch, sucrose and itsderivatives, guar gum, polyethylene glycol and mixtures thereof. 15.Granules according to claim 14 which further contain a diluent agentselected from the group consisting of microcrystalline cellulose,sucrose, dicalcium phosphate starches, lactose, polyols of less than 13carbon atoms such as mannitol, xylitol, sorbitol, maltitol,pharmaceutically acceptable amino acids such as glycin, and theirmixtures, an antistatic agent selected from the group consisting ofmicronised or non micronised talc, fumed silica, precipitated andcolloidal silica, a sweetening agent or a coloring agent.
 16. Granulesaccording to claim 14, which further comprise a disintegrating agentselected from the group consisting of croscarmellose, crospovidone andmixtures thereof or a surfactant which can be an anionic, nonionic,cationic or amphoteric surfactant.
 17. Granules according to claim 15,comprising: from 10% to 95% of fexofenadine, or one of thepharmaceutically acceptable salts thereof, at most 20% by weight of thebinder, relative to the weight of fexofenadine, or one of thepharmaceutically acceptable salts thereof, at most 5% of the antistaticagent, relative to the weight of said granules.
 18. Granules accordingto claim 17, comprising: from 50% to 70% of fexofenadine, or one of thepharmaceutically acceptable salts thereof, at most 10% by weight of thebinder, relative to the weight of fexofenadine, or one of thepharmaceutically acceptable salts thereof, at most 2% by weight of theantistatic agent, relative to the weight of said granules.
 19. Granulesaccording to claim 17, further comprising a diluent agent for thebalance to 100%.
 20. Granules according to claim 18, further comprisinga diluent agent for the balance to 100%.
 21. Granules according to claim14, wherein they are coated with a coating composition containing atleast one coating polymer selected rom the group consisting ofcellulosic polymers such as ethylcellulose, hydroxypropylcellulose andhydroxypropylmethylcellulose, acrylic polymers such as insolubleacrylate amoniomethacrylate copolymer, polyacrylate or methacryliccopolymers, and mixtures thereof.
 22. Granules according to claim 21,wherein the coating composition further contains permeabilizing agents,plasticizers, soluble agents, disintegrating agents or surfactants. 23.Granules according to claim 14 comprising: from 10% to 95% of granulesof fexofenadine, or one of its pharmaceutically acceptable salts. from 5to 90% of a coating polymer, the percentages being expressed by weightrelative to the weight of the granules of the fexofenadine, or one ofits pharmaceutically acceptable salts. from 0 to 10% of a permeabilisingagent, the percentages being expressed by weight relative to the weightof the coating polymer.
 24. Granules according to claim 23 comprising:from 40 to 75% of granules of fexofenadine, or one of itspharmaceutically acceptable salts, from 10 to 70% of a coating polymer,the percentages being expressed by weight relative to the weight of thegranules of the fexofenadine, or one of its pharmaceutically acceptablesalts. from 0 to 10% of colloidal silica as permeabilising agent, thepercentages being expressed by weight relative to the weight of thecoating polymer.
 25. Granules according to claim 24, comprising from 25to 55% of a coating polymer.
 26. Granules according to claim 23,comprising fexofenadine hydrochloride.
 27. Coated granules offexofenadine, or one of its pharmaceutically acceptable salts, accordingto claim 14, which are coated with a coating layer containingfexofenadine wherein the granules and the coating layer comprise eachfrom 70% to 95% by weight of fexofenadine, or one of thepharmaceutically acceptable salts thereof, the balance to 100% beingformed with at least one binder.
 28. Coated granules of fexofenadine, orone of its pharmaceutically acceptable salts, according to claim 27,which are coated with a coating layer containing fexofenadine whereinthe granules and the coating layer comprise each from 80% to 95% byweight of fexofenadine, or one of the pharmaceutically acceptable saltsthereof, the balance to 100% being formed with at least one binder. 29.Process for the preparation of granules according to claim 14 wherein itcomprises the successive steps consisting in: dry mixing themicrocrystals of the fexofenadine or one of its pharmaceuticallyacceptable salts; granulating the mixture obtained in the above step byspraying of a solution or suspension of at least one binder, coating thethus obtained granules with a suspension of a coating composition,drying the thus obtained coated granules.
 30. Process for thepreparation of granules according to claim 15, wherein it comprises thesuccessive steps consisting in: dry mixing the microcrystals of thefexofenadine or one of its pharmaceutically acceptable salts with anantistatic agent or a diluent agent; granulating the mixture obtained inthe above step by spraying of a solution or suspension of at least onebinder, coating the thus obtained granules with a suspension of acoating composition, drying the thus obtained coated granules. 31.Process for the preparation of granules according to claim 27 wherein itcomprises the successive steps consisting in: dry mixing themicrocrystals of the fexofenadine or one of its pharmaceuticallyacceptable salts; granulating the mixture obtained in the above step byspraying of a solution or suspension of at least one binder, applying alayer over the thus obtained granules by spraying thereon a suspension,or a solution comprising fexofenadine, or one of its pharmaceuticallyacceptable salts with at lease one binder, coating the thus obtainedgranules with a suspension of a coating composition, drying the thusobtained coated granules.
 32. Process according to claim 31 wherein itcomprises the successive steps consisting in: dry mixing themicrocrystals of the fexofenadine or one of its pharmaceuticallyacceptable salts with an antistatic agent or a diluent agent;granulating the mixture obtained in the above step by spraying of asolution or suspension of a least one binder, applying a layer over thethus obtained granules by spraying thereon a suspension, or a solutioncomprising fexofenadine, or one of its pharmaceutically acceptable saltswith at least one binder, coating the thus obtained granules withsuspension of a coating composition, drying the thus obtained coatedgranules.
 33. Process for the preparation of tablets according to claim31, comprising the successive steps consisting in: preparing coatedgranules of fexofenadine, or one of its pharmaceutically acceptablesalts, dry mixing coated granules and a mixture of excipients consistingof at least one disintegrating agent and a soluble diluent agent,compressing the mixture of coated granules and excipients into a tablet.34. Process for the preparation of tablets according to claim 31,wherein the mixture of excipients further comprises a lubricant, apermeabilising agent, a swelling agent, sweeteners, an antistatic agent,flavorings and colors. 35-36. (canceled).